Hepatitis C is an infectious disease caused by the Hepatitis C virus (HCV), which primarily affects the liver. The infection is often asymptomatic, but its chronicity can lead to scarring of the liver and, finally, to cirrhosis, which generally becomes evident several years later. In some cases, hepatic cirrhosis may lead to develop liver failure, liver cancer, esophageal and gastric varices. HCV is spread primarily through direct contact with infected blood, often associated with intravenous drugs use, poorly sterilized medical equipments, and blood transfusions.
Hepatitis C virus leads to a chronic infection in 50-80% of HCV-positive people, 40-80% of which are treated. Generally, the pharmacological treatment is recommended in patients with hepatic alterations caused by the virus; the reference treatment is a combination of pegylated interferon alfa and ribavirin, to be taken for a period of 24 or 48 weeks, depending on the HCV virus genotype. It was observed that this therapy leads to improvements in 50-60% of the cases.
In the most difficult phenotypes to treat, these two drugs are used together with boceprevir and telaprevir, bringing the healing rate from 40% to 70%.
Side effects of the treatment are frequent, half of the patients feels flu-like symptoms and a third shows emotional problems, moreover treatment during the first six months proves to be more effective than when hepatitis C becomes chronic.
Sofosbuvir is an EMA and FDA approved drug for the treatment of hepatitis C, it is taken orally and it acts with a mechanism of action directed to the virus life cycle by disrupting its replication, since, being a pan-genotypic inhibitor of HCV RNA-dependent RNA polymerase NS5B prodrug, it can be folded into the HCV RNA of the polymerase NS5B and it can act as a chain terminator. Sofosbuvir has also shown a reduced number of liver disease complications and a reduced number of side effects, compared with patients treated with other treatments.
Sofosbuvir is a compound of formula (I)
chemically known as
isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate, marketed as Sovaldi® and disclosed in U.S. Pat. No. 7,964,580.
U.S. Pat. No. 7,964,580 discloses a process for the preparation of Sofosbuvir of formula (I) by the reaction of a compound of formula 4″, wherein X′ is a leaving group, with a nucleoside analogue of formula 5′

J. Org. Chem., (2011), 76, 8311-8319 discloses the following process for the synthesis of Sofosbuvir, shown in Scheme 1 and in Scheme 2:


The processes disclosed in the the art show several drawbacks due to the presence of two hydroxyl groups in the nucleosidic intermediates reported above, particularly when a Grignard reagent was used for their salification. Said salification reaction, in fact, is non selective and therefore the reaction requires at least two equivalents of Grignard reagent resulting in a double salt which is almost insoluble in the reaction environment and which in turn makes the reaction run and its work up more difficult. Moreover, double salification leads to obtain moderate amounts of two main by-products, such as Sofosbuvir 3′ isomer and the di-substituted compound in 3′ and 5′ position. These two by-products are difficult to separate from Sofosbuvir of formula (I) and, in order to obtain Sofosbuvir of formula (I) having a purity in compliance with the regulatory requirements, long-lasting manufacturing and purification processes are needed.
WO2015/017713 relates to a process for preparing Sofosbuvir, but it does not foresee the use of the intermediate of formula (IV) according to the present invention in the preparation of Sofosbuvir.
WO2015/123352 implicitly discloses the intermediate of formula (IV) used in the process of the present invention, but it gives no hint to use this intermediate for the synthesis of derivatives of Sofosbuvir unprotected at the 3′ position.
Journal of Molecular Catalysis. B, Enzymatic, (2004), 29, 129-132 discloses the selective deprotection of the 5′-O-acetyl of different nucleosides. However, these compounds are not used in the preparation of Sofosbuvir or analogous compound thereof and, in addition, 2′-fluoro ribosides were not tested as possible substrates in D3.